CN104825402A - Gemcitabine containing pharmaceutical composition for injection - Google Patents
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Abstract
Directed at the defects that gemcitabine crude drug is unstable to water and oxidation conditions, the invention designs a gemcitabine containing pharmaceutical composition for injection. Through the technical method of adding a specific dose of polyphenol antioxidant and controlling the water content of a final lyophilized product, the gemcitabine lyophilized preparation for injection with better stability can be obtained. The preparation method for the gemcitabine lyophilized preparation for injection provided by the invention is simple, a conventional preparation method can be adopted for production, and special equipment is not needed. With the significant advantages of easy industrialization, high production efficiency, good stability and controllable quality, etc., the gemcitabine containing pharmaceutical composition for injection has remarkable substantive features and obvious progress.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of medicinal composition for injections containing gemcitabine and its production and use.
Background technology
Gemcitabine hydrochloride (Gemcitabine hydrochloride) is the one novel Difluoronucleosides class antimetabolic tumor medicine of nineteen eighty-three Li Lai company development, English name is Gemcitabine, chemistry 2 '-deoxidation-2 by name ', 2 '-bis-fluorine adenosine (β-isomer), molecular formula is C9H11F2N3O4, and molecular weight is 263.1.Preparation compound used therefor is gemcitabine hydrochloride, and molecular formula is C9H11F2N3O4HCl, and molecular weight is 299.66, and structural formula is as follows:
Gemcitabine mainly kills and wounds DNA and synthesizes (S) phase cell, also can block cell and is in progress to the S phase by G1.It is converted into the activated diphosphate of tool (dFdCDP) and triphosphate (dFdCTP) by nucleoside kinase in cell, suppresses the synthesis of DNA.
On the one hand, dFdCDP suppresses ribonucleotide reductase, and the deoxynucleotide triphosphates making synthetic DNA required (comprising dCTP) generates and reduces.On the other hand, dFdCDP and dCTP competition is mixed in DNA molecular, and in cell, the reduction of dCTP concentration promotes dFdCTP mixing to DNA more.After dFdCTP mixes DNA, can not remove due to archaeal dna polymerase the dFdCTP that mixes and repair DNA chain in extension, the dFdCTP mixed in extended chain can suppress DNA to synthesize further.In addition, it can make the T lymphoblast like cell nuclear dna of CEM be that fragment sample changes, thus causes apoptosis.
Nineteen ninety-five South Africa, Sweden, Holland, the state approval hydrochloride for injection gemcitabine listing such as Australia, within 1996, FDA ratifies the clinical first-line treatment being used for the treatment of nonsmall-cell lung cancer and cancer of pancreas, the hydrochloride for injection gemcitabine of approval of import Lilly company of China in 1999.
Gemcitabine is one of the most effective first-line drug for the treatment of nonsmall-cell lung cancer, there is the advantages such as mechanism of action uniqueness, wide, the high remission rate of antitumor spectra, prolongation life cycle and toxic reaction are low, with other chemotherapeutics without crossing drug resistant and toxic reaction without the feature such as superposing, particularly it effectively can extend the life of patient, improves quality of life of patients.At present, hydrochloride for injection gemcitabine obtains extensive clinical practice in more than 100 countries.
1998, Li Lai company discloses the product description of its commercialized product hydrochloride for injection gemcitabine first in FDA website, and disclose the formula of product: every bottle containing 200mg gemcitabine hydrochloride (representing with free alkali), 200mg mannitol and 12.5mg sodium acetate, be prepared into sterile lyophilized powder.
But gemcitabine crude drug is also unstable, especially can degrade under oxidation and alkali condition produces the following two kinds impurity, impurity A, and chemistry is by name, 2 '-deoxidation-2 ', 2 '-two fluorouracil, structure is as follows:
Impurity B, chemistry is by name, 4-amino-1-(2-deoxidation-2,2-bis-fluoro-alpha-D-erythro form ribofuranose) pyrimidine-2 (1H)-one, and structural formula is as follows:
Especially be hydrolyzed and can degrading under acid condition production impurity A.
To this, research worker proposes different solutions.
Chinese patent CN102302462B discloses a kind of gemcitabine hydrochloride lyophilized formulations; be made up of gemcitabine hydrochloride, freeze drying protectant and antioxidant; wherein: gemcitabine hydrochloride accounts for 20-70 weight portion, freeze drying protectant accounts for 15-60 weight portion, and antioxidant accounts for 0.005-0.5 weight portion.The object adding antioxidant is the stability improving medicine further, and the antioxidant selected in this patent is any one in pyrosulfurous acid hydrogen sodium, citric acid, vitamin C, Cys.Pyrosulfurous acid hydrogen sodium is harmful to human body, many untoward reaction are reported clinically at present, modal is sulphite allergy (especially asthma patient), and symptom is bronchospasm, stridulate, dyspnea, pernicious laryngeal edema, and hypotension, shock are even dead.In addition, also have some research reports, sulphite may cause damage to chromosome and DNA, and the irreversible reaction etc. of cystine linkage in protein.
Chinese patent CN102144981A discloses a kind of gemcitabine hydrochloride lyophilized powder injection and preparation method thereof.This injectable powder comprises gemcitabine hydrochloride 20-30 part, mannitol 5-9 part, sodium acetate 3-10 part, lactose 5-9 part.Although it is simple that this lyophilized injectable powder has process route, freeze-drying time is short, easy to operate advantage, but owing to adding lactose as additives, lactose easily causes " lactose intolerance ", is especially mainly in Asia.In addition, also may introduce the anaphylactogen that the related substance such as residual protein and assorted sugar brings, may there is certain risk in clinical practice.
Chinese patent CN101564381A discloses a kind of gemcitabine hydrochloride lyophilized powder injection, be made up of gemcitabine hydrochloride, mannitol and sodium acetate, wherein gemcitabine hydrochloride and mannitol weight proportion are 1: 0.5-5, and gemcitabine hydrochloride and sodium acetate weight proportion are 1: 0.01-0.1.
To sum up, prior art does not solve the stability problem of gemcitabine preparation completely.
Summary of the invention
As mentioned above, in order to solve the stability problem of gemcitabine preparation, obtain the better gemcitabine preparation of a kind of stability.Inventor is through further investigation, and obtain a kind of composition for injection containing gemcitabine, said composition is principal agent composition with gemcitabine, comprises antioxidant, frozen-dried supporting agent, cosolvent, pH adjusting agent.
Said composition can be prepared into freeze-drying preparation for injection as follows further:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add cosolvent sodium acetate successively, antioxidant, frozen-dried supporting agent mannitol and crude drug gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) to step 3) add in gained solution 0.2% needle-use activated carbon, insulated and stirred 30 minutes;
5) step 4 is got) gained solution, with 0.45um filter, filter, twice;
6) step 5 is got) gained solution, pouring in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
7) step 6 is got) preparation before obtained freeze-drying, insert in freeze dryer, lyophilizing, removing moisture;
8) step 7) freeze-drying process terminates, and inflated with nitrogen, jumps a queue entirely, rolls lid, obtains gemcitabine freeze-drying preparation for injection;
It is characterized in that, described antioxidant is polyphenol compound, and described gemcitabine lyophilizing injection water content is less than 1.0%.
Polyphenol compound refers to that in aromatic hydrocarbon, on phenyl ring, one or more hydrogen atom is optionally substituted by a hydroxyl group generated compound, it is the important secondary metabolite of plant, the polyphenol component of natural origin has various biologic activity, as antioxidation, radioprotective, anticancer, blood pressure lowering etc., very important effect is played to the health of the mankind.
Tea polyphenols has another name called tea tannin, tea polyphenols, is the general name of the polyhydroxyl phenolic compound contained in Folium Camelliae sinensis.Wherein catechin compounds is the bulk composition of tea polyphenols, accounts for 65% ~ 80% of tea polyphenols total amount.Catechin compounds mainly comprises epicatechin, epigallo catechin, L-Epicatechin gallate and nutgall catechin gallic acid ester four kinds of materials.
In tea polyphenols structure, there is active phenolic hydroxyl group, can be used as hydrogen donor, singlet oxygen is reduced into active lower triplet oxygen, thus reduce the generation of oxygen-derived free radicals, and the chain reaction of free radical can be stopped, catch excessive free radical, therefore a kind of desirable antioxidant of Chang Zuowei.Secondly, under neutral, acid condition, the phenolic hydroxyl group of tea polyphenols very easily with metal ion-chelant, thus stop metal ion to the catalytic action of free radical chain reactions.Tea polyphenols and radical reaction generate comparatively stable Phenoxy radical, thus reach the object of direct scavenging free radicals.
Nutgall catechin gallic acid ester (EGCG) is a kind of composition extracted from Chinese green tea, it is the main activity of green tea and water-soluble components, it is the component that in catechin, content is the highest, account for the 9%-13% of green tea gross weight, because have special stereochemical structure, EGCG has very strong antioxidant activity, and antioxidant activity is at least ascorbic more than 100 times, is 25 times of vitamin E.Structural formula is as follows:
After further research, confirm that described is nutgall catechin gallic acid ester containing antioxidant used in the composition for injection of gemcitabine, and its in the composition shared mass percent be 0.3%-0.5%.
Containing gemcitabine 200mg or 1000mg in described unit-dose composition.
Described composition prescription is as follows:
| Supplementary material | Specification 1 | Specification 2 |
| Gemcitabine hydrochloride (in gemcitabine) | 200g | 1000g |
| Mannitol | 200g | 1000g |
| Sodium acetate | 12.5g | 62.5g |
| Nutgall catechin gallic acid ester | 2.0g | 10.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount | In right amount |
| Inject water to | 10000ml | 50000ml |
| pH | 2.5-3.5 | 2.5-3.5 |
| Make altogether | 1000 | 1000 |
Preparation technology is as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) to step 3) add in gained solution 0.2% needle-use activated carbon, insulated and stirred 30 minutes;
5) step 4 is got) gained solution, with 0.45um filter, filter, twice;
6) step 5 is got) gained solution, pouring in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
7) step 6 is got) preparation before obtained freeze-drying, insert in freeze dryer, lyophilizing, removing moisture;
8) step 7) freeze-drying process terminates, and inflated with nitrogen, jumps a queue entirely, rolls lid, obtains gemcitabine freeze-drying preparation for injection, and finished product moisture is less than 1.0%.
Beneficial effect of the present invention is further illustrated by following experiment.
Test one antioxidant select and consumption determine experiment
Known gemcitabine hydrochloride crude drug is stablized illumination and high temperature (60 DEG C, 10 days).By gemcitabine hydrochloride crude drug; Gemcitabine hydrochloride respectively with vitamin C, sodium pyrosulfite, nutgall catechin gallic acid ester mixes, three kinds of antioxidant press mass percent 0.1% separately respectively, 0.3%, 1.0% adds, and the first increment product are dissolved in water for injection, and rear 9 increment product are dissolved in 0.3% hydrogen peroxide solution respectively.Number consecutively A, B, C, D, E, F, G, H, I, J.Dissolve after 1 hour, respectively sampling and measuring, the degraded percentage ratio of gemcitabine hydrochloride, as shown in the table:
| Sample number into spectrum | Degrading quality percent (%) | Sample number into spectrum | Degrading quality percent (%) |
| A(API) | 1.14 | F (0.3% is burnt sub-) | 2.81 |
| B(0.1％Vc) | 4.86 | G (1.0% is burnt sub-) | 2.20 |
| C(0.3％Vc) | 3.36 | H (0.1% does not have) | 1.56 |
| D(1.0％Vc) | 2.49 | I (0.3% does not have) | 1.21 |
| E (0.1% is burnt sub-) | 3.28 | J (1.0% does not have) | 1.08 |
As can be seen from above experimental result, three kinds of antioxidant are under equal in quality percentage ratio condition, and nutgall catechin gallic acid ester oxidation resistance is the strongest, be embodied in H, I, J group sample and the sample adding other two kinds of antioxidant of equal in quality percentage ratio, degrading quality percentage ratio is lower.
In H, I, J tri-groups of samples, along with the raising of antioxidant mass percent, crude drug degraded reduces gradually, and sample I with J degraded percent is almost identical with sample A, illustrate that free oxygen is cancelled completely, and crude drug does not affect by it under these two kinds of mass percent antioxidant conditions.Why degrading quality percent is higher, is that easily degrade, from another side illustration, in product lyophilized formulations, water content can not be too high because crude drug itself is unstable to aqueous solution.
Therefore with this result of the test, can select mass percent be the nutgall catechin gallic acid ester of 0.3%-1.0% as antioxidant, join in the preparation of gemcitabine, to strengthen its stability.For the ease of operation, about 0.5% is selected to add.
Experiment two: freeze-drying preparation for injection preparation and detection.
The determination of eutectic point;
Before Example 1 obtained freeze-drying, gemcitabine hydrochloride is containing drug solns, measure through electric-resistivity method, its eutectic point is-17.5 DEG C, due to embodiment 1 and embodiment 2 two specification piece, its difference is only that packaging material volume used is different, prescription composition is identical, therefore before embodiment 2 obtained freeze-drying, gemcitabine hydrochloride is containing drug solns, and its eutectic point is similarly-17.5 DEG C.
Freeze-dry process confirms:
This product need below eutectic point about 10 DEG C carry out pre-freeze, to make sample fully charge, carry out primary drying afterwards, preliminary removing moisture, finally carry out redrying to remove moisture further, the final water content of this product need reach less than 1.0%, therefore only need after identical pre-freeze and primary drying process, the time of suitable adjustment redrying, required sample can be obtained.
Freeze-dry process is as follows:
1) inlet: gemcitabine hydrochloride pastille solution bottle before embodiment 1 good for fill and embodiment 2 obtained freeze-drying is sent into freeze drying box;
2) pre-freeze: flaggy temperature is set as-40 DEG C, treats that sample temperature drops to about-35 DEG C, keeps 4 hours, and start vacuum pump, drying baker vacuum reaches 20Pa, starts the drying that heats up;
3) first time is dry: control vacuum at 15-30Pa, flaggy temperature is set as-10 DEG C--and 15 DEG C, slowly heat up, after being warming up to design temperature, be incubated 15 hours;
4) second time is dry: flaggy temperature is set as 20 DEG C, after slowly rising to design temperature, maintains 2 hours respectively, 5 hours, 10 hours, 15 hours;
5) lyophilizing terminates, in freeze drying box, pour nitrogen, and tamponade.
Get the sample of above-mentioned test gained two specification different secondary drying time, with Karl_Fischer method working sample moisture, as shown in the table:
| Specification | 2 hours | 5 hours | 10 hours | 15 hours |
| 200mg | 1.3％ | 0.8％ | 0.75％ | 0.7％ |
| 1.0g | 1.5％ | 1.2％ | 0.9％ | 0.85％ |
Learn through this test, final sample water content can control below 1.0% completely.
Test three: injection gemcitabine lyophilized powder and commercially available lyophilized powder accelerated stability contrast test
12 months are stored under two gauge hypodermic gemcitabine lyophilized powders (containing packaging) and commercially available gemcitabine lyophilized powder (containing packaging) put 40 DEG C ± 2 DEG C conditions respectively in Example 1 and embodiment 2, respectively at 0 month, January, March, June, December, sampling and measuring relevant nature, obtain corresponding data, as shown in the table:
As can be seen from upper table data, according to the gemcitabine hydrochloride freeze-drying preparation for injection prepared by embodiment 1 of the present invention and embodiment 2 prescription and technique, under acceleration conditions, after within 12 months, storing, its content, related substance changes all to some extent, but content is all more than 97%, the generation of impurity A % and impurity B % is effectively suppressed, maximum only 0.343% and 0.336%, correspond, in commercially available product, impurity A and impurity B content are then maximum is respectively 0.670% and 0.591%.Unexpectedly 12 months time, in sample, gemcitabine content obviously exceeds corresponding specification gemcitabine listing sample, and all more than 97%, corresponding commercially available product content is then lower than 95%, and other maximum lists are assorted and other total impurities content all decrease.
Gemcitabine freeze-drying preparation for injection as above, as the ejection preparation of gemcitabine, be applicable to treat inoperable late period or transitivity cancer of pancreas and treat Local advancement or Metastatic Nsclc, treatment Advanced non-small cell lung cancer, cancer of pancreas, bladder cancer, breast carcinoma and other entity tumors.
Namely make gemcitabine freeze-drying preparation for injection in storing process by prescription of the present invention and technique, the generation of impurity A and impurity B is effectively suppressed, thus the drug quality improved.Thus make the present invention have outstanding substantive distinguishing features and marked improvement, and there is practicality.
Detailed description of the invention
Beneficial effect of the present invention is further illustrated by following experiment.But be not limited to following embodiment, those skilled in the art does on basis of the present invention, do not depart from the equivalent of flesh and blood of the present invention and substitute or conversion, also all within protection scope of the present invention.
The preparation of embodiment 1 200mg specification gemcitabine freeze-drying preparation for injection
| Supplementary material | Consumption |
| Gemcitabine hydrochloride (in gemcitabine) | 200g |
| Mannitol | 200g |
| Sodium acetate | 12.5g |
| Nutgall catechin gallic acid ester | 2.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount |
| Inject water to | 10000ml |
| pH | 2.5-3.5 |
| Make altogether | 1000 |
Preparation technology is as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) to step 3) add in gained solution 0.2% needle-use activated carbon, insulated and stirred 30 minutes;
5) step 4 is got) gained solution, with 0.45um filter, filter, twice;
6) step 5 is got) gained solution, pouring in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
9) inlet: the step 6 good by fill) gained gemcitabine hydrochloride pastille solution bottle feeding freeze drying box;
10) pre-freeze: flaggy temperature is set as-40 DEG C, treats that sample temperature drops to about-35 DEG C, keeps 4 hours, and start vacuum pump, drying baker vacuum reaches 20Pa, starts the drying that heats up;
11) first time is dry: control vacuum at 15-30Pa, flaggy temperature is set as-10 DEG C-15 DEG C, slowly heats up, and is incubated 15 hours after being warming up to design temperature;
12) second time is dry: flaggy temperature is set as 20 DEG C, after slowly rising to design temperature, maintains 5 hours;
13) lyophilizing terminates, in freeze drying box, pour nitrogen, and tamponade, prick aluminium lid.
The preparation of embodiment 21000mg specification gemcitabine freeze-drying preparation for injection
| Supplementary material | Consumption |
| Gemcitabine hydrochloride (in gemcitabine) | 1000g |
| Mannitol | 1000g |
| Sodium acetate | 62.5g |
| Nutgall catechin gallic acid ester | 10.0g |
| 0.1M hydrochloric acid or sodium hydroxide | In right amount |
| Inject water to | 50000ml |
| pH | 2.5-3.5 |
| Make altogether | 1000 |
Preparation technology is as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) to step 3) add in gained solution 0.2% needle-use activated carbon, insulated and stirred 30 minutes;
5) step 4 is got) gained solution, with 0.45um filter, filter, twice;
6) step 5 is got) gained solution, pouring in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
9) inlet: the step 6 good by fill) gained gemcitabine hydrochloride pastille solution bottle feeding freeze drying box;
10) pre-freeze: flaggy temperature is set as-40 DEG C, treats that sample temperature drops to about-35 DEG C, keeps 4 hours, and start vacuum pump, drying baker vacuum reaches 20Pa, starts the drying that heats up;
11) first time is dry: control vacuum at 15-30Pa, flaggy temperature is set as-10 DEG C--and 15 DEG C, slowly heat up, after being warming up to design temperature, be incubated 15 hours;
12) second time is dry: flaggy temperature is set as 20 DEG C, after slowly rising to design temperature, maintains 10 hours;
13) lyophilizing terminates, in freeze drying box, pour nitrogen, and tamponade, prick aluminium lid.
Claims (9)
1. the medicinal composition for injections containing gemcitabine, said composition is main component with gemcitabine, comprises antioxidant, frozen-dried supporting agent mannitol, cosolvent sodium acetate, pH adjusting agent,
Said composition can be prepared into freeze-drying preparation for injection as follows further:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add cosolvent sodium acetate successively, antioxidant, frozen-dried supporting agent mannitol and crude drug gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) in step 3) gained solution, the needle-use activated carbon of 0.2% is added, insulated and stirred 30 minutes;
5) get step 4) gained solution, with 0.45um filter, filter, twice;
6) getting step 5) gained solution, pour in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
7) get preparation before step 6) obtained freeze-drying, insert in freeze dryer, lyophilizing, removing moisture;
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid, obtains gemcitabine freeze-drying preparation for injection;
It is characterized in that, described antioxidant is polyphenol compound, and described gemcitabine lyophilizing injection water content is less than 1.0%.
2. the medicinal composition for injections as claimed in claim 1 containing gemcitabine, it is characterized in that, described antioxidant is nutgall catechin gallic acid ester
.
3. the medicinal composition for injections as claimed in claim 2 containing gemcitabine, is characterized in that, described nutgall catechin gallic acid ester
shared mass percent is 0.3%-0.5% in the composition.
4. the medicinal composition for injections containing gemcitabine as described in claims 1, is characterized in that in unit-dose composition containing gemcitabine 200mg or 1000mg.
5. the medicinal composition for injections containing gemcitabine as described in claim 1-4, is characterized in that becoming freeze-drying composition for injection by following formula preparation:
。
6. the medicinal composition for injections containing gemcitabine as described in claim 1-4, is characterized in that becoming freeze-drying composition for injection by following formula preparation:
。
7. the medicinal composition for injections containing gemcitabine as described in claim 1-4, is characterized in that being prepared into freeze-drying composition for injection as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) in step 3) gained solution, the needle-use activated carbon of 0.2% is added, insulated and stirred 30 minutes;
5) get step 4) gained solution, with 0.45um filter, filter, twice;
6) getting step 5) gained solution, pour in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
7) get preparation before step 6) obtained freeze-drying, insert in freeze dryer, lyophilizing, removing moisture;
8) step 7) freeze-drying process terminates, and inflated with nitrogen is jumped a queue entirely, rolls lid, obtains gemcitabine freeze-drying preparation for injection, and finished product moisture is less than 1.0%.
8. the medicinal composition for injections containing gemcitabine as claimed in claim 5, is characterized in that being prepared into freeze-drying composition for injection as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) in step 3) gained solution, the needle-use activated carbon of 0.2% is added, insulated and stirred 30 minutes;
5) get step 4) gained solution, with 0.45um filter, filter, twice;
6) getting step 5) gained solution, pour in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
9) inlet: step 6) gained gemcitabine hydrochloride pastille solution bottle good for fill is sent into freeze drying box;
10) pre-freeze: flaggy temperature is set as-40 DEG C, treats that sample temperature drops to about-35 DEG C, keeps 4 hours, and start vacuum pump, drying baker vacuum reaches 20 Pa, starts the drying that heats up;
11) first time is dry: control vacuum at 1 5-30 Pa, flaggy temperature is set as-10 DEG C-15 DEG C, slowly heats up, and is incubated 15 hours after being warming up to design temperature;
12) second time is dry: flaggy temperature is set as 20 DEG C, after slowly rising to design temperature, maintains 5 hours;
13) lyophilizing terminates, in freeze drying box, pour nitrogen, and tamponade, prick aluminium lid.
9. the medicinal composition for injections containing gemcitabine as claimed in claim 6, is characterized in that being prepared into freeze-drying composition for injection as follows:
1) get gemcitabine hydrochloride crude drug to pulverize, for subsequent use;
2) get the water for injection of full dose 80%, add sodium acetate successively, nutgall catechin gallic acid ester, mannitol and gemcitabine hydrochloride, stir, make dissolving;
3) using 0.1M hydrochloric acid and sodium hydroxide as pH adjusting agent, regulate pH value of solution to 2.5-3.5, and be settled to full dose;
4) in step 3) gained solution, the needle-use activated carbon of 0.2% is added, insulated and stirred 30 minutes;
5) get step 4) gained solution, with 0.45um filter, filter, twice;
6) getting step 5) gained solution, pour in suitable volumetric control bottle, partly jump a queue, is preparation before lyophilizing;
9) inlet: step 6) gained gemcitabine hydrochloride pastille solution bottle good for fill is sent into freeze drying box;
10) pre-freeze: flaggy temperature is set as-40 DEG C, treats that sample temperature drops to about-35 DEG C, keeps 4 hours, and start vacuum pump, drying baker vacuum reaches 20 Pa, starts the drying that heats up;
11) first time is dry: control vacuum at 1 5-30 Pa, flaggy temperature is set as-10 DEG C--and 15 DEG C, slowly heat up, after being warming up to design temperature, be incubated 15 hours;
12) second time is dry: flaggy temperature is set as 20 DEG C, after slowly rising to design temperature, maintains 10 hours;
13) lyophilizing terminates, in freeze drying box, pour nitrogen, and tamponade, prick aluminium lid.
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| CN201510198335.3A CN104825402B (en) | 2015-04-23 | 2015-04-23 | A kind of medicinal composition for injections containing gemcitabine |
| CN201810050733.4A CN108066291A (en) | 2015-04-23 | 2015-04-23 | Gemcitabine pharmaceutical composition |
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| CN108440625A (en) * | 2018-04-18 | 2018-08-24 | 日照市普达医药科技有限公司 | A kind of Difluoronucleosides class antimetabolite anticarcinogen destroying cellular replication |
| CN109464403A (en) * | 2018-12-07 | 2019-03-15 | 江苏瑾辉生物科技有限公司 | Theaflavih digallate (TFDG) monomer freeze drying powder injection and preparation method thereof |
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| CN109758467B (en) * | 2019-03-08 | 2020-12-25 | 中国农业科学院兰州兽医研究所 | Application of gemcitabine in preparation of drugs for preventing foot-and-mouth disease virus infection |
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| CN108066291A (en) | 2018-05-25 |
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